Related Experiment Video

Updated: May 30, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
06:07

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

2.5K

Isoxazole-pyrimidine derivatives as TACC3 inhibitors: A novel modality to targeted cancer therapy

Deniz Lengerli1, Özge Akbulut Çalışkan2, Kübra Çalışkan1

  • 1Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey.

Bioorganic Chemistry
|January 31, 2025
PubMed

Insights

Researchers developed novel compounds to inhibit transforming acidic coiled-coil 3 (TACC3) for cancer therapy. Compound 13b shows improved metabolic stability and bioavailability, acting as a promising TACC3 inhibitor for various cancers.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Transforming acidic coiled-coil 3 (TACC3) is a therapeutic target for breast, ovarian, and lung cancers.
  • Previous TACC3 inhibitor BO-264 had limited metabolic stability.
  • Improving metabolic stability while retaining potency is crucial for drug development.

Purpose of the Study:

  • To design and synthesize novel analogs of BO-264 to enhance metabolic stability and maintain TACC3 inhibitory potency.
  • To identify a lead compound with improved pharmacokinetic properties and a favorable safety profile.
  • To validate TACC3 as the biological target of the developed compounds.

Main Methods:

  • Synthesis of sixty-two novel compounds based on the BO-264 chemotype.
  • Structure-activity relationship (SAR) analysis to guide modifications.
  • In vitro assays to assess metabolic stability, potency, and safety.
  • Western blotting to detect markers of mitotic arrest, apoptosis, and DNA damage (p-Histone H3, cleaved PARP, p-H2AX).
  • Drug Affinity Responsive Target Stability (DARTS) assay to identify the drug target.

Main Results:

  • Structural modifications on the phenyl-isoxazole and morpholine groups improved metabolic stability and preserved potency.
  • Compound 13b demonstrated a sevenfold increase in metabolic stability and improved bioavailability.
  • Compound 13b induced mitotic arrest, apoptosis, and DNA damage.
  • DARTS assay confirmed TACC3 as the direct biological target of compound 13b.

Conclusions:

  • Compound 13b represents an advanced lead compound for TACC3 inhibitor development.
  • The optimized TACC3 inhibitors show potential for treating cancers with elevated TACC3 expression.
  • Further development of 13b could lead to novel therapeutic strategies for cancer treatment.
Keywords:
Anticancer agentBreast cancerIsoxazolePyrimidineTACC3

More Related Videos

Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction09:44

Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction

Published on: January 29, 2019

10.0K
Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

11.0K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.4K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
464
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.6K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
4.8K
Drugs that Stabilize Microtubules01:15

Drugs that Stabilize Microtubules

Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
2.0K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.2K